Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02018055 |
| Other study ID # |
TALOS-AMI |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
February 14, 2014 |
| Est. completion date |
January 21, 2021 |
Study information
| Verified date |
March 2021 |
| Source |
The Catholic University of Korea |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to evaluate the efficacy and safety of clopidogrel in stabilized
patients with acute myocardial infarction (AMI) who performed percutaneous coronary
intervention (PCI) with drug-eluting stents (DES) compared with ticagrelor.
In this study, 2,590 patients with AMI who underwent PCI with DES and took dual antiplatelet
therapy as aspirin and ticagrelor during 1 month from index PCI will be randomized to
aspirin+ticagrelor versus aspirin+ clopidogrel during 11 months.
Description:
1. Study design Pospective, multi-center, randomized, open trial
2. Study Objective To investigate the efficacy and safety of switching from ticagrelor to
clopidogrel in stabilized patients with AMI with no adverse events during the first
month after an index PCI
3. Study Drug Test drug: Clopidogrel Control drug: Ticagrelor
4. Study Disease Acute myocardial infarction: ST-segment elevation MI (STEMI) and
non-ST-segment elevation MI (NSTEMI)
5. Study Population 2590 (loss to follow-up: 10 %) -Test group: 1295 -Control group: 1295
6. SAMPLE SIZE CALCULATIONS
The present study is designed to show non-inferiority for the treatment group with
aspirin plus clopidogrel versus the control group with aspirin plus ticagrelor. The
sample size is based on the combined occurrence rate of ischaemic and bleeding events
between 1 and 12 months after AMI. According to the PLATO investigators, the event rate
of the primary efficacy endpoint including CV death, MI or stroke was 5.28% in the
ticagrelor group and 6.60% in the clopidogrel group between 1 and 12 months after the
index event1. There were no reported data on the bleeding event rate associated with
ticagrelor from 1 to 12 months after AMI, especially the BARC bleeding rate at the time
of the present study design. Therefore, we assumed the event rate of BARC 2, 3 or 5
bleeding from the event rates of non-coronary artery bypass graft (CABG)-related PLATO
major or minor bleeding because the content of BARC 2, 3 or 5 bleeding was conceptually
quite similar with non-CABG-related PLATO major or minor bleeding. With regard to the
assumption of the bleeding rate from 1 to 12 months after the index PCI, we calculated
the expected bleeding rate using a proportional equation under the assumption that the
occurrence ratio of non-CABG-related major bleeding of the first 30 days to that of
after 30 days and the ratio of non- CABG-related major or minor bleeding of the first 30
days to that of after 30 days could be equal. Thus, for the event rate of BARC 2, 3 or 5
bleeding associated with ticagrelor from 1 to 12 months after AMI, the event rate was
assumed from the event rates of non-CABG-related PLATO major or minor bleeding during a
year of ticagrelor therapy (8.7%) and non-CABG-related major bleeding of the first 30
days (2.47%) and after 30 days (2.17%) in the PLATO trial. For the event rate of BARC 2,
3 or 5 bleeding associated with clopidogrel from 1 to 12 months after AMI, the event
rate was assumed from the event rates of non- CABG-related PLATO major or minor bleeding
during a year of clopidogrel therapy (7.0%) and non-CABG-related major bleeding of the
first 30 days (2.21%) and after 30 days (1.65%) in the clopidogrel group of the PLATO
trial7. After applying a proportional equation, we estimated that the BARC 2, 3 or 5
bleeding would be 4.07% in the ticagrelor group and 2.99% in the clopidogrel group.
Thus, the expected event rate of the primary endpoint from 1 to 12 months after the
index PCI was 9.35% (ischaemic event of 5.28% + bleeding event of 4.07%) in the
ticagrelor group and 9.59% (ischaemic event of 6.6% + bleeding event of 2.99%) in the
clopidogrel group. We chose the non-inferiority margin in accordance with clinical
judgement and other relevant studies with a non-inferiority design for the present study
design. The non-inferiority margin of two contemporary trials of antiplatelet treatment
after PCI that were available up to that time was equivalent to a 40% increase in the
expected event rate16,17. The steering committee decided that the non-inferiority margin
in our study should be less than a 40% increase compared to the expected event rate of
the control group. After considering clinically acceptable relevance and the feasibility
of study recruitment, we finally selected the non-inferiority margin of 3.0%, which was
equivalent to a 32% increase in the expected event rate. Sample size calculations (PASS
13; NCSS, LLC, Kaysville, UT, USA) were initially performed based on a one-sided α of
0.025 and a power of 80%. To achieve these goals, a total of 2,230 patients was needed.
After considering a follow-up loss rate of 10%, there should be at least 1,644 per group
and a total of 3,288 patients. However, while the study was actively underway, the
government policy on investigator-initiated trials (ITTs) changed: it was decided not to
allow national health insurance to charge for the medical care costs of participating
patients in ITTs. Soon after, the government was forced to permit the application of
national health insurance to ITTs on the condition that researchers should obtain
approval for their studies by the head of the Health Insurance Review and Assessment
service. However, during this turmoil, researchers' willingness to register patients had
been compromised, and they could not register patients as planned within the period.
Thus, the steering committee held an emergency meeting with data and safety monitoring
board (DSMB) members and independent statisticians and decided to recalculate the sample
size for the timely completion of the trial. In recalculating the sample size, we
adopted a one-sided α of 0.05 instead of 0.025. According to the CONSORT statement of
non-inferiority and equivalence in trials18, a one-sided α of 0.05 was acceptable for
the non-inferiority clinical trials. Moreover, in the large-scale TROPICAL-ACS (Testing
Responsiveness to Platelet Inhibition Chronic Antiplatelet Treatment for ACS) trial (one
of the famous CV drug trials similar to the TALOS-AMI trial), the researchers adopted a
one-sided α of 0.05 for the sample size calculation4. Furthermore, of 110 CV
non-inferiority trials published in JAMA, The Lancet or the New England Journal of
Medicine from 1990 to 2016, a one-sided α was 0.05 in 66 trials19. Based on this
external harsh environment and a review of the sample size calculation in previous
large-scale randomised trials published in high-impact journals, we recalculated the
sample size by using a one-sided α of 0.05, a power of 80% and a follow-up loss rate of
10%. As such, the sample size was reduced from 3,288 to 2,590 (1,295 patients in each
group)
7. Study Design
1) Screening period
To conduct screening AMI patients based on the inclusion/exclusion criteria who (1) have been
treated with ticagrelor+aspirin for at least 30±7 days after an index PCI, (2) received full
explanation of the study details, (3) given informed consent To randomize eligible subjects
within 30±7 days after AMI undergoing PCI with newer generation DES, and receiving aspirin
and ticagrelor to the treatment and control groups in a 1:1 ratio.
2)Treatment period
Enrolled patients receive clopidogrel 75mg + aspirin 100 mg (treatment group) or ticagrelor
90mg bid +aspirin 100mg treatment (control group) for 11 months (post-AMI 1 month to 12
months) and evaluation safety and efficacy by conducting physical examination, checking vital
sign, and collecting adverse events at post-PCI 3M, 6M, 12M visits.
Labboratory and imaging tests, which undergo according to the medical judgment of each
investigator during the study period, are collected by reviewing medical records or EMR.
8. Randomization
1. Subject Assignment and Randomization
Randomization will be performed to ensure the scientific validity of the clinical test.
This will maximize the comparability of the test and control group and eliminate the
subjectivity of the researchers in subject group assignment. Before PCI, a 250-325mg
loading dose of aspirin is given to patients who are naïve to treatment and all patients
receive a loading dose of ticagrelor 180mg. Discharge medication consists of aspirin
100mg once and ticagrelor 90mg twice per day. All patients receive treatment with
aspirin plus ticagrelor for 1 month after the index PCI (screening period). At 30 ±
7days after index PCI, eligible patients were randomly assigned either to the 1) aspirin
100 mg plus clopidogrel 75mg daily (treatment group) or 2) aspirin 100 mg plus
ticagrelor 90mg twice daily (control group) in a 1:1 ratio. Randomization will occur
centrally. To randomize a patient, the investigative site will enter the subject into
the designated electronic system and obtain the treatment assignment (clopidogrel +
aspirin or ticagrelor + aspirin) in a 1:1 ratio. At 1 month visit after AMI, eligible
subjects were assigned to each treatment group following an access to the interactive
web-based response system (IWRS, Medical Excellence Inc., Seoul, Korea) by the
investigator or designee. Randomization sequence was created by an independent
statistician using SAS 9.3 (SAS Institute Inc. Cary, NC, USA) statistical software and
was stratified by study center and type of AMI (STEMI or NSTEMI) and with a 1:1
allocation using hidden random block size.
2. Dosage and Method Test (Clopidogrel): 75mg oral administration, once a day Control
(Ticagrelor): 1 tablet (90mg) oral administration, twice a day
3. Switching protocol (ticagrelor to clopidogrel) In the control treatment group, when
switching from ticagrelor to clopidogrel, patients take a 75mg clopidogrel without
loading dose at the time of the next scheduled dose after the final dose of ticagrelor
(eg, ≈12 hours from last dose of ticagrelor). The steering committee decided this
switching strategy of no loading dose based on the concept that our study population
would be at stable status at the time point of randomization (30 days after index PCI).
The data safety and monitoring board (DSMB) approved this switching strategy on the
condition that initial 100 enrolled patients in the treatment group should be monitored
daily during first 7days for the occurrence of adverse clinical events by telephone
interviews. Thereafter, DSMB reviewed the clinical data of the initial 100 patients in
the treatment group and recommended continuation of the study according to the original
protocol. After randomization, patients continue the same medication for 11 months
according to their group allocation (treatment period, Figure 1). Patients are evaluated
at 3 (2 months after randomization), 6 (5 months after randomization), and 12 (11months
after randomization) months after index PCI and monitored for the occurrence of the
clinical events.
9. Statistical Analysis
1. Efficacy Test Variable Analysis
1. Primary endpoint analysis Efficacy Test The non-inferiority test between 1 and 12 months
after AMI will be based on the Kaplan-Meier estimates. A 95% two-sided confidence
interval will be computed for the difference event rate (clopidogrel + aspirin) - event
rate (ticagrelor + aspirin). The clopidogrel group will be judged as non-inferior to the
ticagrelor if the upper confidence limit is less than the predetermined non-inferiority
margin of 3% (absolute risk difference).
The hypothesis of non-inferiority test will be based on the difference of proportions.
Let rT denote the true event proportion in the test arm (clopidogrel + aspirin) between
1 and 12 months, and rC denote the true event proportion in the control arm (ticagrelor
+ aspirin) between 1 and 12 months. The hypotheses are H0: rT - rC≥Δ HA: rT - rC<Δ
TheΔis the non-inferiority margin, and is taken to be 0.03. The test will be performed
as a one-sided test at alpha=0.05.
The null hypothesis shall be rejected at alpha=0.05 if the one-sided p-value is less
than 0.05. When this occurs, the upper limit of the two-sided 95% confidence interval
will be less than 3%.
If the non-inferiority analysis passed the acceptance criterion, a superiority analysis
will be performed. Statistical superiority is achieved when the upper limit of the
two-sided 95% confidence interval of the risk difference is less than 0%. The type I
error for this analysis is protected by the non-inferiority analysis, and no alpha
adjustment would be appropriate
Subgroup analyses will be performed by the primary endpoint categorized by type of AMI
(STEMI vs NSTEMI), Subgroup analyses will be performed by the primary endpoint
categorized by Type of AMI (STEMI vs NTEMI), Gender, Age (>=75 vs <75), Diabetes, LVEF
(>=40% vs <40%), eGFR (>=60 vs <60), type of implanted stents (Xience vs Resolute vs
Synergy stents), Bleeding risk according to the ARC criteria (high vs low bleeding
risk), CYP2C19 loss-of-function carrier status (carrier vs non-carrier).
The primary analysis population for primary and secondary endpoints will be the
Intention-to-Treat (ITT) population. The primary endpoint analysis will also be
performed on the Per Protocol (PP) population as subsequent analysis.
A primary endpoint analysis stratified by the institutions as a sensitivity analysis.
Strata will be divided by the accrual number of institution based on quartiles.
Implement noninferiority validation based on the tolerance limit after collecting
cumulative occurrence rate of MACCE (CV death, MI, stroke) + BARC bleeding (type 2, 3,
or 5) post 1M-1Y PCI and checking 95% confidence interval of [Ticagrelor occurrence rate
- Clopidogrel occurrence rate]. If the upper value of the 95% confidence interval is
less than 3% of the noninferiority tolerance limit, Clopidogrel is perceived noninferior
to Tricagrelor. Present the cumulative limit method, Kaplan-Meier curve and conduct
log-rank test to check the difference between two groups.
2. Main Secondary Endpoint Analyses
The secondary endpoints will be composed of two families. The first family consists of the
composite endpoint of MACCE (CV death, MI, stroke) plus BARC bleeding (type 2, 3, or 5). The
second family will consist of MACCE plus BARC bleeding (type3, or 5), MACCE, and BARC
bleeding (type 2, 3, or 5). The endpoints from the second family will be tested
hierarchically, thereby maintaining the study-wise alpha level. These secondary endpoints
will only be tested if both the primary composite endpoint and BARC bleeding are significant
at non-inferiority analysis, and superiority analysis. Composite endpoint of MACCE plus BARC
bleeding (type 3, or 5) will be tested first, and only if this is significant, the composite
endpoint of MACCE only will be tested afterwards. BARC bleeding (type 2, 3, or 5) will be
tested only if both of the above endpoints are tested significant.
10. Analysis Population
1. The Intent to Treat (ITT) Population
The ITT population is defined as all randomized patients at 1 month after AMI,
regardless of their adherence with the entry criteria, regardless of treatment they
actually received, and regardless of subsequent withdrawal from treatment or deviation
from the protocol19. Only some specific reasons that might cause an exclusion of a
patient from the ITT population:
No treatment was applied at all No data are available after randomization
2. The Per Protocol (PP) Population
The PP population is the subset of ITT population consisting of all patients who receive
and retain the treatment during 12 months after PCI19. Some specific reasons that might
cause an exclusion of a patient from the PP population:
Violation of entry criteria including inclusion and exclusion criteria Withdrawal of
consent Concomitant treatment of oral anticoagulant agent (vitamin-K antagonists or
novel oral anticoagulants such as dabigatran, rivaroxaban, apixaban, or edoxaban) during
the study period Poor compliance -Conversion from ticagrelor + aspirin to clopidogrel +
aspirin during RCT procedure and vice versa
- Discontinuation of test or control drugs for 7 days or longer
3. * In the cases of withdrawal of consent, concomitant treatment of oral anticoagulation
agent and poor compliance, their data will be used for statistical analyses until such
events occur.
11. Final enrollment number
The initially planned enrollment number of patients was 2,590, however, the actual number of
registered patient was larger than this, which was 2,697. The randomization of the current
trial was performed using interactive web-based response system and patients were
competitively enrolled in 32 institutions. Despite the competitive registration among
participating institutions, the random system did not have a lock on it, resulting in a
registration of 107 more patients than initially planned number. When DSMB closely monitored
the status of additionally registered subjects, its members agreed that there were no safety
issues to them and they got an approval of IRB for using the data of additionally registered
patients for the statistical analyses.
